Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[MeSci]

If a difference in gut flora was found my first thought would be that it would be likely to be due to a change in gut motility or secretory patterns from autonomic dysfunction or immunological changes in the gut wall. In scleroderma there is a change in gut flora because of reduced motility. My malabsorption is presumably associated with some sort of change in flora pattern as a hang over from functional changes due to some immunological reaction to tropical organisms ten years ago. So I was thinking that a shift in flora might be a useful marker of some specific gut dysfunction. If ME patients had bacteria present never found in normal people that would be different, but I suspect this is unlikely to be the case.

For those interested in gut-ME/CFS connections, these 3 papers may be of interest, ditto their reference lists, and citing articles, which can be found if you look in PubMed. I've included quotes from the papers.

Lakhan SE, Kirchgessner A. (2010) Gut inflammation in chronic fatigue syndrome

Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis...If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder.

http://www.nutritionandmetabolism.com/content/pdf/1743-7075-7-79.pdf


Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, Logan AC (2009) A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome

Research shows that patients with CFS and other so-called functional somatic disorders have alterations in the intestinal microbial flora.

http://www.gutpathogens.com/content/1/1/6


Maes M, Leunis JC. (2008) Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria

There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS).

http://integrativehealthconnection....1/Leaky-gut-in-CFS-treatment-of-leaky-gut.pdf

 

[Jill]

Edwards said ::
I had not seen the Tan paper before. The question is why it was never followed up. Presumably it did not prove repeatable?

If its one thing I know about CFS research is that so many interesting papers have been produced , but no-one follows them up. The reasons are various - mainly funding. It has always saddened me to see this. So please don't presume anything Prof Edwards. Maybe email Tan yourself to find out - that is the only sure fire way of finding things out in a field like this.
The reduced blood volume work of Bell & Streeton was stunning, but it too was never followed up (Streeton died and Bell retired) . Each CFS research group are chewing away at their own part of this elephant, then if funds dry up no one seems to ever pick up the loose ends. Its just the way its been I'm afraid.

 

[Jonathan Edwards]

Edwards said ::
I had not seen the Tan paper before. The question is why it was never followed up. Presumably it did not prove repeatable?

If its one thing I know about CFS research is that so many interesting papers have been produced , but no-one follows them up. The reasons are various - mainly funding. It has always saddened me to see this. So please don't presume anything Prof Edwards. Maybe email Tan yourself to find out - that is the only sure fire way of finding things out in a field like this.
The reduced blood volume work of Bell & Streeton was stunning, but it too was never followed up (Streeton died and Bell retired) . Each CFS research group are chewing away at their own part of this elephant, then if funds dry up no one seems to ever pick up the loose ends. Its just the way its been I'm afraid.

Yes, I think that is at least part of the story. However, I see a significant trend towards changing that. Lipkin has maybe set the trend in repeating results. Lots of people are interested in repeating the Norwegian findings. Others are looking to repeat other immunological findings. Several people are looking at gut microbes. I think things will firm up.

There may be a Catch 22 in repeating the Tan data in that some researchers would exclude autoantibody positive cases from their CFS study cohort before they start! We have a definition problem here. My experience is that you do not solve a definition problem like that by sitting down in a committee and coming up with a new definition. Rather you advance the science a few steps and then have good reasons to define new groupings. It isn't easy but it can be done.

 

[user9876]

It does look as if one could reasonably expect that. I have tended to think Fluge and Mella would have been lucky to have more than 50% B cell related cases and maybe the extra two patients were the matching placebo responders for the two controls that responded. But then even diseases where we know everyone's symptoms are B cell related we do not get 100% response rates. I think there is actually quite a lot of evidence around suggesting that the majority of ME is B cell related but I want to err on the side of caution. I certainly hope that in a year or two we will have a much clearer idea on that.

Do you think that we are likely to see one B cell related problem or do you think there could be a number of different underlying mechanisms leading to different (but overlapping) symptom sets.

Yes, there are several situations where it seems that an autoimmune loop is set up months or years before any symptoms. In RA this is thought to be the usual situation. Sometimes rather trivial features are present for years before typical symptoms appear. The loops that I envisage would be able to feed off other loops so over a period of time the disease may evolve and become more complex. This is quite often seen in RA. In lupus all sorts of shifts in symptoms and signs can occur. In a number of conditions Raynaud's phenomenon seems to occur before the major symptoms become apparent. And so on. Hyperthyroidism can change to hypothyroidism and vice versa. I have even seen classical long term RA turn into giant cell arteritis, with the RA disappearing.

Presumably there is a trigger that causes the loop to suddenly get worse.

I was wondering if looking at the various fluctuations in ME would give a clue to the cycles involved. Having practically no knowledge of biology it is hard for me to think about such cycles let alone have an intuition about what is reasonable. But I was wondering about a cycle where over exertion seems to create a relapse. My initial thought was this was cycles in the autonomic system getting pushed into the wrong equilibrium but I was then wondering are there some proteins or other stuff released in the body due to over exertion and could this be what antibodies are binding with.(I was thinking that this combined compound could then be doing damage or blocking receptors etc). I assume that such compounds would gradually be removed from the body allowing a limited recovery until the next load of activity. But if the level that people's bodies were to recognize over exertion reduced with function then this could become a loop keeping people at a low functional level. Getting a virus initially might act to initiate such a process (by setting a low exertion level) and hence appear as a trigger even though minor symptoms were already present.

 

[Jonathan Edwards]

Do you think that we are likely to see one B cell related problem or do you think there could be a number of different underlying mechanisms leading to different (but overlapping) symptom sets.



Presumably there is a trigger that causes the loop to suddenly get worse.

I was wondering if looking at the various fluctuations in ME would give a clue to the cycles involved. Having practically no knowledge of biology it is hard for me to think about such cycles let alone have an intuition about what is reasonable. But I was wondering about a cycle where over exertion seems to create a relapse. My initial thought was this was cycles in the autonomic system getting pushed into the wrong equilibrium but I was then wondering are there some proteins or other stuff released in the body due to over exertion and could this be what antibodies are binding with.(I was thinking that this combined compound could then be doing damage or blocking receptors etc). I assume that such compounds would gradually be removed from the body allowing a limited recovery until the next load of activity. But if the level that people's bodies were to recognize over exertion reduced with function then this could become a loop keeping people at a low functional level. Getting a virus initially might act to initiate such a process (by setting a low exertion level) and hence appear as a trigger even though minor symptoms were already present.

I think there may be a whole group of B cell related problems hiding under the name of ME. However, if they all depend on B cell loops there may be a common way to treat them all, with some variations. As you say, though, there may well be overlap. So we could say that rheumatoid arthritis is really six overlapping problems in the sense that the detailed causal mechanisms do vary from person to person. Old fashioned 'disease' names may not be ideal for understanding these things, but it is hard for any of is to avoid using them to an extent.

We have already had some discussion about cycles of symptoms and how they might indicate mechanisms. A B cell response takes several days to build up, at minimum, and once antibodies are made they tend to stay around for weeks, so some of the symptom cycles in ME seem too short for that. On the other hand the sort of mechanism you are thinking of sounds very plausible. There may be signal molecules that get sent out over a period of hours or days, that should then be followed by 'switch off' signals and this might fail. TNF and IL-10 tend to switch each other off - as an example. Maybe if TNF is blocked IL-10 gets pumped out for far too long. Something like that could make sense. And a virus could start things off for a new cytokine cycle.

 

[rosie26]

Brilliant having you here Prof Edwards. ! Thanks.

 

[Ecoclimber]

It is evident that gut flora plays an important if not a key role in the development of certain types of diseases. Research still has to find what that key role is as the jury is still out and very few replication studies have been conducted.

After talking to top gastroentologists researchers in Seattle, understanding the interaction between gut flora, diseases, the autoimmune system and the brain is still an emerging field that is not fully understood by researchers. But, I thought I would throw some links up here to indicate that there is an emerging field of research on this topic.This is a bit outside my area of expertise.

Natural Intestinal Flora Involved in the Emergence of Multiple Sclerosis, Study Finds

Gut Bacteria Could Play Key Role in Development of Type 2 Diabetes

An Altered Gut Microbiota Can Predict Diabetes

Gut Microbes Closely Linked to Proper Immune Function, Other Health Issues

The Gut Microbiota

NIH Awards $22M for Human Microbiome Project's Second Phase

NIH HUMAN MICROBIOME PROJECT

There is one remarkable antecdotal story. Dr. Terry Wahl, clinical professor of medicine at the University of Iowa Carver College of Medicine in Iowa City, Iowa, came down with progressive MS for 35 years and by changing her diet is recovering n=1. https://www.ncbi.nlm.nih.gov/pubmed/19918474

Study Reveals Changes in Gut Microflora Can Affect Brain Function

Not to be outdone on getting in on some good poopy research and the fad of the moment, the Good MouseDoctor over at Barts and London and the MSers

The Next Science Fad?-The Microbiome
When we talk about science and how it follows science fashion, we often said jokingly that we have "flavours of the month" to reflect science thought. The question is- will this flavour leave a nasty taste in the mouth?

Based on the debate about priorities in the last couple of days.
After I said in a comment "you may be asked to eat it", you asked what is "Faecal Transplantation".

This relates to the Microbiome or gut bacteria. You need a gut flora to aid digestion and so we see lots of adverts for nutriceuticals on "good bacteria"

MouseDoctor "Is this the New Aspirin of the 21st Century? Lets see!"

Eco

 

[lansbergen]

[quote="Jonathan Edwards, post: 387847, Maybe if TNF is blocked IL-10 gets pumped out for far too long. Something like that could make sense. [/quote]

Or raised il 10 protects against worse.

 

[Marco]

Although the details are yet to be confirmed, Ian Lipkin suggests that leptin is raised in ME/CFS patients (not uniquely by any means) and one previous study has correlated fatigue levels with leptin levels in ME/CFS.

I wonder if Jonathan Edwards could comment on reported associations between elevated leptin and an increased risk of autoimmune disease?

PS - apologies - they do tend to mention a few of your personal bugbears :

Restricted leptin antagonism as a therapeutic approach to treatment of autoimmune diseases.

http://www.ncbi.nlm.nih.gov/pubmed/21349802

Leptin in Autoimmune Diseases

http://link.springer.com/chapter/10.1007/978-1-59745-370-7_7

The Leptin Connection: Regulatory T Cells and Autoimmunity

http://www.sciencedirect.com/science/article/pii/S1074761307001409

Edited to add :

This recent paper may be more relevant to discussion of rituximab :

Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans

http://www.immunityageing.com/content/10/1/3

 

[Marco]

Sorry Jonathan Edwards but your name just popped up

Do self-perpetuating B lymphocytes drive human autoimmune disease?

Could leptin play a role in the extended survival of autoreactive B lymphocytes?

Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice.

B lymphocytes appear to be more susceptible to the antiapoptotic effects of leptin, and they show higher surface expression of ObR, compared with T cells.

http://www.ncbi.nlm.nih.gov/pubmed/16751422

 

[MeSci]

We have already had some discussion about cycles of symptoms and how they might indicate mechanisms. A B cell response takes several days to build up, at minimum, and once antibodies are made they tend to stay around for weeks, so some of the symptom cycles in ME seem too short for that. On the other hand the sort of mechanism you are thinking of sounds very plausible. There may be signal molecules that get sent out over a period of hours or days, that should then be followed by 'switch off' signals and this might fail. TNF and IL-10 tend to switch each other off - as an example. Maybe if TNF is blocked IL-10 gets pumped out for far too long. Something like that could make sense. And a virus could start things off for a new cytokine cycle.

Do you know how a decreased physiological pH affects some of the chemical compounds you are studying?

It appears that over-exertion produces hyperlactaemia in ME/CFS sufferers, and the direct and/or downstream effects are involved in causing PEM and also perhaps - at least from multiple anecdotal evidence - perpetuating a pathological loop and thus the illness itself.

 

[Legendrew]

Do you know how a decreased physiological pH affects some of the chemical compounds you are studying?

It appears that over-exertion produces hyperlactaemia in ME/CFS sufferers, and the direct and/or downstream effects are involved in causing PEM and also perhaps - at least from multiple anecdotal evidence - perpetuating a pathological loop and thus the illness itself.

I'd expect lactate to be a general hindrance of all proteins considering the denaturing effect a lower pH tends to have but I doubt it to be a major concern - certainly it seems more of an effect of whatever mechanisms are happening rather than a cause, other than muscle fatigue which is likely as a result of higher lactate production implying to me a lowered threshold for aerobic respiration and anaerobic having to take up the slack as it were, it all ties in with the mitochondrial dysfunction that has been observed on several occasions.

From a personal perspective I see two mechanisms leading to the build-up of lactate; higher production in the muscles under trivial levels of exertion and seemingly lowered threshold for removal of excess lactate perhaps tying into the lowered peripheral blood circulation as has been suggested in the past. It's that old problem of cause and effect again, where symptoms are caused by one thing but that in turn is caused by another and so it continues...

It's interesting just how many systems appear to be effected and it should be telling us something about what is going on, the trouble being that the more systems effected the trickier it appears to tie it all down to one thing - certainly the idea of multiple B-cell problems is an interesting one.

 

[MeSci]

I'd expect lactate to be a general hindrance of all proteins considering the denaturing effect a lower pH tends to have but I doubt it to be a major concern - certainly it seems more of an effect of whatever mechanisms are happening rather than a cause, other than muscle fatigue which is likely as a result of higher lactate production implying to me a lowered threshold for aerobic respiration and anaerobic having to take up the slack as it were, it all ties in with the mitochondrial dysfunction that has been observed on several occasions.

From a personal perspective I see two mechanisms leading to the build-up of lactate; higher production in the muscles under trivial levels of exertion and seemingly lowered threshold for removal of excess lactate perhaps tying into the lowered peripheral blood circulation as has been suggested in the past. It's that old problem of cause and effect again, where symptoms are caused by one thing but that in turn is caused by another and so it continues...

It's interesting just how many systems appear to be effected and it should be telling us something about what is going on, the trouble being that the more systems effected the trickier it appears to tie it all down to one thing - certainly the idea of multiple B-cell problems is an interesting one.

I'd forgotten about the denaturing effect. I would think that that could actually be quite significant. What say you, Jonathan Edwards?

I have also recently been thinking and reading up a little on hypovolaemia - something that seems common with us. Although this paper relates mainly to critical care situations, there are some statements that may be relevant to us, for example:

Compensatory systemic release of catecholamines promotes peripheral vasoconstriction, increased cardiac contractility and tachycardia.

Having had numerous episodes of tachycardia the other night, I was also trying to figure out the reason. I was also very polyuric that night. That is one thing that can cause hypovolaemia. The waves of feeling wired and jittery would appear likely to be due to systemic release of catecholamines.

Finally, anerobic metabolism occurring in response to reduced perfusion may produce acidosis

So - hypovolaemia can cause acidosis. Over-exertion can cause acidosis. Acidosis can denature proteins. Over-exertion also appears to cause polyuria in some of us, which could lead to/perpetuate hypovolaemia.

More from the paper:

Ischemia develops with diminished GI perfusion, especially in the mucosal layer of the gut (Fig. 1). Mucosal integrity may be compromised. Impaired gut barrier function may allow translocation of bacteria and endotoxins"

I think we have the bones of a few positive feedback loops here.

Could Prof Edwards suggest any immunological markers that might play a part?

 

[Bob]

I haven't read this paper in detail, and I haven't studied its cited research.
The reason I'm posting it is because it collates some ME/CFS autoimmunity literature, for example, in the extract below.

Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics
Gerwyn Morris and Michael Maes
17 September 2013
BMC Medicine 2013, 11:205
doi:10.1186/1741-7015-11-205
http://www.biomedcentral.com/1741-7015/11/205/abstract

"Many individuals with ME/CFS show several indicators of autoimmune responses. Anti-cardiolipin antibodies have been reported in people with ME/CFS [211,212]. Konstantinov et al. [213] reported the presence of autoantibodies to nuclear envelope antigens. Anti-neuronal antibody levels are elevated in ME/CFS patients with neurologic abnormalities [214]. Other indicators include elevated antibody titers towards phospholipids, gangliosides and serotonin; anti-lamine SS DNA as well as anti-68/48 kDa and microtubule-associated proteone [215-217]. In addition to these increased antibody levels that are also observed in MS, patients with ME/CFS show various other markers of autoimmunity. Thus, autoantibodies against the muscarinic cholinergic receptor, mu-opioid receptor, 5-hydroxytryptamine (5-HT; serotonin) receptor 1A and dopamine receptor D2 have all been detected in ME/CFS patients [218] (for a review see [9])."

The full paper can be read here:
http://www.biomedcentral.com/1741-7015/11/205

 

[MeSci]

I'd forgotten about the denaturing effect. I would think that that could actually be quite significant. What say you, Jonathan Edwards?

Answering my own message as I have been continuing to ponder the issues, and thought - would denatured proteins increase autoimmune disposal-type activity? So I did a search for 'denatured proteins autoimmunity' and got this interesting article.

Some pertinent bits:

disrupting the fine folded structure of the protein leads not just to loss of microscopic activity but also to macroscopic changes in properties. Most obviously, when proteins become denatured their solubility is decreased. Look at egg whites used to make a meringue – egg white is a solution of dissolved protein that is clear and almost colourless, but after whipping for several minutes to denature the protein, it changes into a stiff, white suspension. Cooking eggs achieves a similar conversion.

This turns out to be a headache for cells. Once the protein comes out of solution it is difficult, if not impossible to handle. The enzymes responsible for degrading proteins, called proteases, struggle to get a handle on the precipitated mass of denatured protein. Without “special measures”, these nodules of denatured protein would accumulate and eventually kill the cell.

The aberrant proteins and organelles are surrounded by a double membrane to form an autophagosome, in a process regulated by PI3Kinase and several "atg" proteins first discovered in yeast. The autophagosome then matures into a lysosome where the contents are crudely degraded by acid hydrolases.

Every disease you can imagine from Alzheimer's Disease to diabetes, depression to osteoporosis, schizophrenia to autoimmunity has misregulation of these ancient pathways that control the disposal of damaged and unwanted cellular components at their core.

(my bolding)

So could acidosis be key in perpetuating a feedback loop involving protein denaturing and consequent (aberrant?) autoimmune activity?

 

[Legendrew]

I was just doing a little reading and came across the following article about a girl with kleine-levin syndrome. It certainly sounds an unusual illness but the strange thing that struck me was that the onset is often triggered by a viral type illness such as cold or flu. Sure enough a little more research shows autoimmune theories have been suggested numerous time: certainly I can see similarities with narcolepsy which has previously been discussed. Certainly I think all of these diseases need more research but it's interesting to see an acute viral onset in this.
http://www.ncbi.nlm.nih.gov/pubmed/12473762
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021925/

 

[Jonathan Edwards]

I was just doing a little reading and came across the following article about a girl with kleine-levin syndrome. It certainly sounds an unusual illness but the strange thing that struck me was that the onset is often triggered by a viral type illness such as cold or flu. Sure enough a little more research shows autoimmune theories have been suggested numerous time: certainly I can see similarities with narcolepsy which has previously been discussed. Certainly I think all of these diseases need more research but it's interesting to see an acute viral onset in this.
http://www.ncbi.nlm.nih.gov/pubmed/12473762
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021925/

I had never heard of K-L syndrome but it must be telling us something very important I guess. Maybe you can work out what it is Andrew! There are probably no true autoimmune processes commoner in males, although other immune disturbances like ankylosing spondylitis are. I am stumped.

 

[Jonathan Edwards]

Although the details are yet to be confirmed, Ian Lipkin suggests that leptin is raised in ME/CFS patients (not uniquely by any means) and one previous study has correlated fatigue levels with leptin levels in ME/CFS.

I wonder if Jonathan Edwards could comment on reported associations between elevated leptin and an increased risk of autoimmune disease?

PS - apologies - they do tend to mention a few of your personal bugbears :

Restricted leptin antagonism as a therapeutic approach to treatment of autoimmune diseases.

http://www.ncbi.nlm.nih.gov/pubmed/21349802

Leptin in Autoimmune Diseases

http://link.springer.com/chapter/10.1007/978-1-59745-370-7_7

The Leptin Connection: Regulatory T Cells and Autoimmunity

http://www.sciencedirect.com/science/article/pii/S1074761307001409

Edited to add :

This recent paper may be more relevant to discussion of rituximab :

Increased activation and cytokine secretion in B cells stimulated with leptin in aged humans

http://www.immunityageing.com/content/10/1/3

Ah, those bugbears again! I feel a draught of hot air all of a sudden. But, seriously, leptin does sound an interesting candidate for study. I doubt ageing is the reason for autoimmunity being commoner as you get old though. In RA incidence falls after 80, as it does for breast cancer I think. This is an odd phenomenon that can be explained on a cumulative chance with time model but not on an ageing model. (If is a chance model with a genetically determined threshold then there comes a point when all the susceptible people have had what they are going to get and beyond a certain age you can expect incidence to decline.) Lupus is probably more genetically determined than RA and incidence falls even earlier, although oestrogen levels may be relevant there.

All that said, even if the speculation is barking up the wrong trees, autoimmunity involving leptin looks as if it could get some loops going.

 

[Jonathan Edwards]

Do you know how a decreased physiological pH affects some of the chemical compounds you are studying?

It appears that over-exertion produces hyperlactaemia in ME/CFS sufferers, and the direct and/or downstream effects are involved in causing PEM and also perhaps - at least from multiple anecdotal evidence - perpetuating a pathological loop and thus the illness itself.

I would not expect pH to have much of an effect to be honest and denaturation is not going to occur at physiological levels I think. I amy be wrong but unless you are very ill your pH regulation tends to be pretty reliable.

 

[Marco]

I doubt ageing is the reason for autoimmunity being commoner as you get old though. In RA incidence falls after 80, as it does for breast cancer I think. This is an odd phenomenon that can be explained on a cumulative chance with time model but not on an ageing model. (If is a chance model with a genetically determined threshold then there comes a point when all the susceptible people have had what they are going to get and beyond a certain age you can expect incidence to decline.) Lupus is probably more genetically determined than RA and incidence falls even earlier, although oestrogen levels may be relevant there.

Nor ageing per se perhaps but leptin secreting white adipose tissue?

Percentage body fat tends to increase with age up to a point. The very old tend to have trouble maintaining weight. Plus of course females tend to naturally have a higher proportion of body fat.